Proteinase, proteolysis, proteasome, ubiquitin, aminopeptidase, peptidase, neuropeptide, angiotensin.
Our laboratory is involved in research on the properties and functional significance of proteolytic enzymes. In recent years it has become clear that proteolytic enzymes mediate many important cellular processes including: the activation and inactivation of regulatory molecules and transcription factors, the biosynthesis and inactivation of neuropeptides, and apoptosis. The therapeutic significance of proteolytic enzymes is seen by the use of their inhibitors as drugs. This is exemplified by the ever-increasing application of angiotensin converting enzyme inhibitors in the treatment of cardiovascular diseases and the introduction of HIV protease inhibitors for the treatment of AIDS. The design and synthesis of inhibitors of proteolytic enzymes is one of the major aims of our research program.
The proteasome (multicatalytic proteinase complex), first isolated and characterized in our laboratory almost twenty years ago, is a high molecular mass proteolytic molecule found in relatively high concentrations in the cytosol and nucleus of all eukaryotic cells. The explosive growth of research on the proteasome is accounted for by evidence of its essential role in many fundamental cellular processes. Basic questions about the relationship of the structure of the proteasome to its function and its mechanism of regulation in vivo, remain unanswered. We are studying the mechanism of activation of the proteasome by several endogenous nuclear activator proteins and the physiological significance of endogenous activators.
We have purified, characterized, cloned and expressed a new acidic amino acid preferring aminopeptidase. One of its important biological substrates is the vasoactive peptide angiotensin. This enzyme is abundant and widely distributed. Its sequence is highly conserved. It is the first identified and only known mammalian member of the M18 family of metalloproteinases. We are studying the relationship of its subunit structure to its catalytic activity, the nature of its endogenous substrates and the regulation of its enzymatic activity.
Tang G, Perng MD, Wilk S, Quinlan R, Goldman JE. Oligomers of mutant glial fibrillary acidic protein (GFAP) Inhibit the proteasome system in alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition. J Biol Chem 2010 April; 285(14): 10527-10537.
Dunys J, Kawarai T, Giaime E, Wilk S, Herrant M, Auberger P, St George-Hyslop P, Alves da Cost C, Checler F. Study on the putative contribution of caspases and the proteasome to the degradation of Aph-1a and Pen-2. Neurodegener Dis 2007; 4(2-3): 156-3.
Longenecker KL, Stewart KD, Madar DJ, Jakob CG, Fry EH, Wilk S, Lin CW, Ballaron SJ, Stashko MA, Lubben TH, Yong H, Pireh D, Pei Z, Basha F, Wiedeman PE, von Geldern TW, Trevillyan JM, Stoll VS. Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors. Biochemistry 2006 Jun 20; 45(24): 7474-82.
Alves Da Costa C, Dunys J, Brau F, Wilk S, Cappai R, Checler F. 6-Hydroxydopamine but not 1-methyl-4-phenylpyridinium abolishes alpha-synuclein anti-apoptotic phenotype by inhibiting its proteasomal degradation and by promoting its aggregation. J Biol Chem 2006 Apr 7; 281(14): 9824-31.
Dunys J, Kawarai T, Wilk S, St George-Hyslop P, Alves da Costa C, Checler F. Catabolism of endogenous and overexpressed APH1a and PEN2: evidence for artifactual involvement of the proteasome in the degradation of overexpressed proteins. Biochem J 2006 Mar 1; 394(Pt 2): 501-9.
Morty RE, Bulau P, Pelle R, Wilk S, Abe K. Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts. Biochem J 2006 Mar 15; 394(Pt 3): 635-45.
Checler F, Alves da Costa C, Ayral E, Andrau D, Dumanchin C, Farzan M, Hernandez JF, Martinez J, Lefranc-Jullien S, Marambaud P, Pasini A, Petit A, Phiel C, Robert P, St George-Hyslop P, Wilk S. JLK inhibitors: isocoumarin compounds as putative probes to selectively target the gamma-secretase pathway. Curr Alzheimer Res 2005 Jul; 2(3): 327-34.
Wilk S, Wilk E, Magnusson RP. Identification of histidine residues important in the catalysis and structure of aspartyl aminopeptidase. Arch. Biochem. Biophys. 2002 Nov; 407(2): 176-183.
Petit A, Pasini A, Alves Da Costa C, Ayral E, Hernandez JF, Dumanchin-Njock C, Phiel CJ, Marambaud P, Wilk S, Farzan M, Fulcrand P, Martinez J, Andrau D, Checler F. JLK isocoumarin inhibitors: selective gamma-secretase inhibitors that do not interfere with notch pathway in vitro or in vivo. J Neurosci Res 2003 Nov 1; 74(3): 370-377.
Orlowski M, Wilk S. Ubiquitin-independent proteolytic functions of the proteasome. Arch Biochem Biophys 2003 Jul 1; 415(1): 1-5.
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